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      Prognostic and predictive factors of eribulin efficacy in heavily pretreated patients affected by metastatic breast cancer: correlation with tumor biology and previous therapies

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          Abstract

          Background

          Eribulin mesylate is currently approved in the United States and Europe for the treatment of metastatic breast cancer (MBC).

          Scope

          The objective of this retrospective study is to find specific predictive criteria related to patient or tumor characteristics in order to select patients that might benefit the most from eribulin and define the correct treatment sequence.

          Findings

          Forty-four patients with MBC who received eribulin in third or subsequent lines of therapy in a single Italian center were considered eligible. Patients were stratified by body mass index, hormonal/HER2 status, and previous therapies. Primary endpoint was progression free survival (PFS), whereas secondary endpoint was disease control rate (DCR).

          A longer PFS was found in patients with hormone-positive tumors ( p=0.0051), in HER2-negative cases ( p=0.037), and in overweight patients ( p=0.0015). No difference in efficacy was observed when eribulin was administered in third or subsequent lines of therapy. Significantly longer PFS ( p<0.0001) and higher DCR ( p=0.035) were achieved by patients previously treated with paclitaxel-bevacizumab in comparison to those pretreated with other drug combinations or with anthracyclines. Prior treatment with nab-paclitaxel seems to have a detrimental effect on PFS ( p=0.0008).

          Conclusion

          Hormone and HER2 status seems a good predictive and prognostic indicator of response to eribulin. Efficacy seems independent from the number of prior therapies, and it is not influenced by prior endocrine treatments and anthracyclines-containing regimens. On the other hand, sensitivity to a prior treatment with paclitaxel-bevacizumab might be predictive of response to eribulin.

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          Most cited references17

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          The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth.

          E7389, which is in phase I and II clinical trials, is a synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B. Whereas its mechanism of action has not been fully elucidated, its main target seems to be tubulin and/or the microtubules responsible for the construction and proper function of the mitotic spindle. Like most microtubule-targeted antitumor drugs, it inhibits tumor cell proliferation in association with G(2)-M arrest. It binds to tubulin and inhibits microtubule polymerization. We examined the mechanism of action of E7389 with purified microtubules and in living cells and found that, unlike antimitotic drugs including vinblastine and paclitaxel that suppress both the shortening and growth phases of microtubule dynamic instability, E7389 seems to work by an end-poisoning mechanism that results predominantly in inhibition of microtubule growth, but not shortening, in association with sequestration of tubulin into aggregates. In living MCF7 cells at the concentration that half-maximally blocked cell proliferation and mitosis (1 nmol/L), E7389 did not affect the shortening events of microtubule dynamic instability nor the catastrophe or rescue frequencies, but it significantly suppressed the rate and extent of microtubule growth. Vinblastine, but not E7389, inhibited the dilution-induced microtubule disassembly rate. The results suggest that, at its lowest effective concentrations, E7389 may suppress mitosis by directly binding to microtubule ends as unliganded E7389 or by competition of E7389-induced tubulin aggregates with unliganded soluble tubulin for addition to growing microtubule ends. The result is formation of abnormal mitotic spindles that cannot pass the metaphase/anaphase checkpoint.
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            Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors.

            The contribution of bone marrow-derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobilization of CEPs, which home to the viable tumor rim that characteristically remains after such therapy. Disruption of this CEP spike by antiangiogenic drugs or by genetic manipulation resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity. These findings also provide a mechanistic rationale for the enhanced efficacy of VDAs when combined with antiangiogenic drugs.
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              Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents.

              Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1alpha and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.
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                Author and article information

                Journal
                Drugs Context
                Drugs Context
                DIC
                Drugs in Context
                BioExcel Publishing Ltd
                1745-1981
                1740-4398
                2017
                08 November 2017
                : 6
                : 212506
                Affiliations
                [1 ]Department of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano (MI), Italy
                [2 ]Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
                Author notes
                Correspondence: Sabrina Rossi, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano (MI), Italy. sbrn.rossi85@ 123456gmail.com
                Article
                dic-6-212506
                10.7573/dic.212506
                5699107
                8376d76c-6911-4c05-88a5-c0d65c62a22f
                Copyright © 2017 Rossi S, Cassano A, Strippoli A, Schinzari G, D’Argento E, Basso M, Barone C

                Distributed under the terms of the Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

                History
                : 19 July 2017
                : 26 September 2017
                : 27 September 2017
                Categories
                Original Research

                breast neoplasms,neoplasm metastasis,body mass index,obesity receptors,progesterone,receptors,estrogen,triple negative breast neoplasms,bevacizumab,paclitaxel,taxoids

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